Increasing evidence suggests that initial cancer development is due to a rare population of cells, termed cancer stem cells (CSCs) (also known as “tumor-initiating cells”, or “tumor side-populations”, or “cancer stem-like cells”) that are able to initiate and sustain this disease. These cells have indeed been demonstrated to be responsible for tumorigenesis, cancer metastasis, and cancer reoccurrence in particular cancers. Cancer stem cells have self-renewal capacity and they can differentiate into multiple cell types, although the equilibrium between self-renewal and differentiation potential shifts towards enhanced self-renewal, leading to limited differentiation capacity.
Conventional chemotherapies and radiotherapies are known to kill differentiated or differentiating cells, which form the bulk of the tumor (but that are unable to regenerate tumors). However, the population of cancer stem cells remains unaffected by said treatments and often causes a relapse of the disease.
In this context, it is imperative that anti-cancer therapies include strategies affecting preferentially CSCs. As a matter of fact, by targeting cancer stem cells, it will be possible to treat patients with aggressive and non-resectable tumors, as well as preventing tumor metastasis and recurrence.
Moreover, the identification of molecules that target CSCs in a selective manner, i.e., while sparing non-cancerous or normal stem cells, is critical to provide new anti-cancer drugs having few side effects.
It is therefore important to identify and validate pathways that are selectively implicated in cancer stem cell self-renewal and survival. Yet, though multiple pathways underlying properties of embryonic or adult stem cells have been already elucidated, few pathways have been identified for cancer stem cell self-renewal and survival.
Glioblastoma multiforme (GBM) is the most frequent and malignant primary tumor of the central nervous system in adults (60 000 cases/year in Europe and US). It has been proposed that GBM tumors derive from a small fraction of cells that constitute a reservoir of self-sustaining cells with the exclusive ability to self-renew and maintain the tumor, called glioblastoma stem-like cells (GSCs) (Singh et al, 2003). Regardless of the brain tumor ontogeny, GSCs might be involved in resistance to radiotherapies and contribute to tumor recurrence and aggressiveness (Bao et al, 2006). Furthermore, alterations in GSC levels affect tumor growth in experimental models of glioma (Piccirillo et al, 2006). Very few therapeutic protocols exist for this disease and, despite major clinical efforts, median survival rates from the time of diagnosis range between 12 and 15 months, and fewer than 3% of patients survive more than 5 years (Fisher et al, 2007).
In this context, the inventors identified pathways that regulate specifically the self-renewal and survival of CSCs—and in particular of GSCs. They now propose to screen for compounds that are able to block specifically these pathways, said compounds being efficient for treating patients with aggressive tumors, with minor side effects.
More precisely, the inventors highlight for the first time the essential interplay between the Akt/mTOR and STAT3 signaling pathways in self-renewal and survival of cancer stem-like cells such as GSCs. These pathways are activated by the endothelial-produced Apelin which operates through the APJ and GP130 membrane co-receptors. The results below show that the Apelin/APJ/Gp130 signaling nexus operates as a niche-specific signal that sustains tumour initiation and progression, suggesting that Apelin is a druggable paracrine factor in glioblastoma. As a matter of fact, compounds impairing the protein interaction of Apelin on its coreceptors APJ/GP130 (thereby inhibiting the Akt/mTor and STAT3 pathways) in GSCs lead to their apoptosis and thus refrain tumor progression and recurrence.